ja207809b_si_001.pdf (1.58 MB)
The Elusive 5′-Deoxyadenosyl Radical in Coenzyme-B12-Mediated Reactions
journal contribution
posted on 2016-02-22, 07:45 authored by Denis Bucher, Gregory M. Sandala, Bo Durbeej, Leo Radom, David M. SmithVitamin B12 and its biologically active counterparts
possess the only examples of carbon–cobalt bonds in living
systems. The role of such motifs as radical reservoirs has potential
application in future catalytic and electronic nanodevices. To fully
understand radical generation in coenzyme B12 (dAdoCbl)-dependent
enzymes, however, major obstacles still need to be overcome. In this
work, we have used Car–Parrinello molecular dynamics (CPMD)
simulations, in a mixed quantum mechanics/molecular mechanics (QM/MM)
framework, to investigate the initial stages of the methylmalonyl-CoA-mutase-catalyzed
reaction. We demonstrate that the 5′-deoxyadenosyl radical
(dAdo•) exists as a distinct entity in this reaction,
consistent with the results of extensive experimental and some previous
theoretical studies. We report free energy calculations and first-principles
trajectories that help understand how B12 enzymes catalyze
coenzyme activation and control highly reactive radical intermediates.